The platinum-based chemotherapeutic agent cisplatin (cis-diammine-dichloro-platinum) has been well established in clinical treatment regimens due to its effectiveness on human tumor cells, such as in the context of ovarian, lung, testicular and breast cancer (Kelland, 2007; Lee et al, 2004; Sirohi et al, 2008). Cisplatin triggers formation of intra-strand and inter-strand DNA-adducts, which leads to cell cycle arrest, followed by apoptosis (Kelland, 2007). However, an inherent or acquired resistance to cisplatin is a major clinical drawback for patients who relapse after an initial favorable responses (Galluzzi et al, 2012). Cisplatin resistance is a complex problem which involves multiple pathways including increased drug efflux, evasion of apoptotic pathways, a bypass of the replication checkpoint, increased cell proliferation and increased DNA damage repair (Galluzzi et al, 2012). To overcome the drug resistance against platinum-based chemotherapy, combination therapies with peroxisome proliferator-activated receptor gamma (PPARγ) agonists, the thiazolidinediones (TZDs), have been performed. The basis for this approach is the growth inhibitory effect of these PPARγ agonists on transformed cells through both PPARγ-dependent and -independent pathways (Blanquicett et al, 2008; Mueller et al, 1998; Palakurthi et al, 2001; Satoh et al, 2002). PPARγ is a member of the nuclear hormone receptor superfamily and a key transcription factor for adipogenesis. It is also involved in various physiological processes, such as cell proliferation, angiogenesis, inflammation and lipid partitioning (Tontonoz & Spiegelman, 2008). Combination therapies with TZDs have been shown to display beneficial effects on cancer cell death, while also leading to a reduction of overall systemic toxicity to these chemotherapeutic regimens (Girnun et al, 2008; Girnun et al, 2007; Tikoo et al, 2009). However, the detailed molecular basis underlying the beneficial effects of TZDs to platinum treatment has yet to be documented prior to the present invention.
In the tumor microenvironment, both stromal and cancer cells contribute to various types of extracellular matrix (ECM) proteins to actively remodel the microenvironment favorably for tumor growth and metastasis. Such ECM proteins include fibronectin, laminin, collagen I (COL1), collagen IV (COL4) and collagen VI (COL6), and these ECM components are markedly modulated in response to chemotherapy (Dangi-Garimella et al, 2011; Sherman-Baust et al, 2003; Su et al, 2007). They have been suggested to cause drug resistance in solid tumors, including small-cell lung cancer, ovarian cancer, pancreatic cancer and breast cancer (Heileman et al, 2008; Rintoul & Sethi, 2001; Sherman-Baust et al, 2003; Shields et al, 2012) through multiple pathways. These include an induction of anti-apoptotic pathways (Sethi et al, 1999), decreased drug transport (Netti et al, 2000) and increased survival signals, such as those mediated through integrin-based pathways (Jean et al, 2011). COL6 is composed of three alpha chains; α1, α2 and α3. Particularly, the α3 chain of COL6 (COL6A3) has been highlighted as a promising candidate triggering drug resistance against platinum-based therapeutics since its levels are vastly increased in the cisplatin-resistant cancer cells in vitro (Sherman-Baust et al, 2003; Varma et al, 2005). Nevertheless, the more detailed mechanism underlying how COL6A3 regulates drug-resistance has remained elusive. Furthermore, compositions useful for inhibiting COL6A3 have yet to be characterized in connection with chemotherapy.